1-oxo-2- (phenylsulphonylamino) pentylpiperidine derivatives, their preparation and their therapeutic application

ABSTRACT

The present invention provides a compound of formula (I) ##STR1## in which R 1  represents a hydrogen atom or a (C 1  -C 4 )alkyl group, R 2  represents a hydrogen atom or a straight or branched (C 1  -C 4 )alkyl group, R 3  represents a straight or branched (C 1  -C 7 )alkyl group, a group --(CH 2 ) n  OCH 3  (where n is 1, 2 or 3) or a group --CH 2  O(C 2  H 4  O) m  CH 3  (where m is 1, 2 or 3), R 4  represents a hydrogen atom or a halogen atom, R 5  represents a straight or branched (C 1  -C 4 )alkyl group and A represents phenyl or heterocyclic group optionally substituted with one or more substituents independently chosen from halogen atoms and straight or branched (C 1  -C 4 )alkyl, straight or branched (C 1  -C 4 )alkoxy and trifluoromethyl groups, or a cyclo(C 5  -C 8 ) alkyl group, in the form of the free base or of a pharmaceutically acceptable addition salt thereof, a process for their preparation and their use in the treatment of thrombosis and thrombotic complications.

This is a division of application Ser. No. 08/577,935, filed Dec. 22,1995.

The present invention relates to1-oxo-2-(phenylsulphonylamino)pentylpiperidine derivatives, to theirpreparation and to their therapeutic application.

The present invention provides a compound formula (I) ##STR2## in whichR₁ represents a hydrogen atom or a (C₁ -C₄)alkyl group,

R₂ represents a hydrogen atom or a straight or branched (C₁ -C₄)alkylgroup,

R₃ represents a straight or branched (C₁ -C₇)alkyl group, a group--(CH₂)_(n) OCH₃ (where n is 1, 2 or 3) or a group --CH₂ O(C₂ H₄ O)_(m)CH₃ (where m is 1, 2 or 3),

R₄ represents a hydrogen atom or a halogen atom,

R₅ represents a straight or branched (C₁ -C₄)alkyl group and

A represents either a phenyl or heterocyclic group optionallysubstituted with one or more substituents independently chosen fromhalogen atoms and a straight or branched (C₁ -C₄)alkyl, straight orbranched (C₁ -C₄)alkoxy and trifluoromethyl groups, or a cyclo(C₅-C₈)alkyl group, in the form of the free base or of a pharmaceuticallyacceptable addition salt thereof.

Preferred compounds according to the invention are those in which:

R₃ represents a straight or branched (C₁ -C₇)alkyl group, and Arepresents a pyridyl, thienyl or furyl group, optionally substitutedwith one or more substituents independently chosen from halogen atomsand straight or branched (C₁ -C₄)alkyl, straight or branched (C₁-C₄)alkoxy and trifluoromethyl groups.

The compounds of the invention possess 3 asymmetric centres. Thepreferred configuration of the piperidyl group is 2R,4R!.

The preferred configuration of the central amino acid part ##STR3## isS!.

The compounds may exist in the form of free bases or addition salts withpharmaceutically acceptable acids.

All of these forms form part of the invention.

In the schemes which follow, the --CPh₃ group represents thetriphenylmethyl group.

According to the invention, the compounds of formula (I) may in generalbe synthesized according to Scheme 1.

A sulphonic acid of formula (II), in which A and R₄ are as definedabove, is reacted with an acid chloride of formula (III) in which R₃ isas defined above, generally in an aprotic solvent such asdichloromethane in the presence of a base such as pyridine, followed byaddition of triethylamine, generally in excess, to obtain atriethylamine salt of formula (IV); the compound of formula (IV) is thenreacted with trifluoroacetic anhydride to obtain a compound of formula(V), from which a compound of formula (VI) is prepared by the action ofphosphorus pentachloride generally in a solvent such as dichloromethane;finally, the compound of formula (VI) is reacted with a compound offormula (VII), in which R₁ represents a hydrogen atom or a (C₁ -C₄)alkylgroup, R₂ represents a straight or branched (C₁ -C₄)alkyl group and R₅represents a straight or branched (C₁ -C₄)alkyl group, generally in anaprotic solvent such as dichloromethane in the presence of a base suchas triethylamine, then the imidazolyl ring is deprotected and thetrifluoroacetyl residue is removed in an acidic medium such as aceticacid/ethanol or acetic acid/tetrahydrofuran/water mixture at reflux, toobtain a compound of formula (I) in which R₂ represents a straight orbranched (C₁ -C₄)alkyl group. ##STR4##

If a compound of formula (I) in which R₂ represents a hydrogen atom isdesired, the corresponding compound of formula (I) in which R₂represents a straight or branched (C₁ -C₄)alkyl group is saponifiedunder standard conditions known to those skilled in the art.

In a variant of the process, illustrated in general in Scheme 2, toprepare the compounds of formula (Ia), in which R'₃ represents astraight or branched (C₁ -C₇)alkyl group, a compound of formula (II),which is generally first reacted with triethylamine to form atriethylamine salt, is reacted with an acid chloride of formula (IIIa)or with an anhydride of formula (IIIb), to obtain a symmetrical imide,either in the form of the triethylamine salt of formula (Va) or in theform of the corresponding amine in which case the triethylamine salt offormula (Va) is then prepared, which salt is treated with phosphoruspentachloride to obtain a compound of formula (VIa) which is reactedwith a compound of formula (VII) generally in an aprotic solvent such asdichloromethane in the presence of a base such as triethylamine, thenthe imidazolyl ring is deprotected and one of the residues --COR'₃ isremoved in an acidic medium such as acetic acid/ethanol, aceticacid/water or acetic acid/tetrahydrofuran/water mixture at reflux, toobtain a compound of formula (Ia) in which R₂ represents a straight orbranched (C₁ -C₄)alkyl group. ##STR5##

If a compound of formula (Ia) in which R₂ represents a hydrogen atom isdesired, the corresponding compound of formula (Ia) in which R₂represents a straight or branched (C₁ -C₄)alkyl group is saponifiedunder standard conditions known to those skilled in the art.

It is also possible to use the process illustrated in general by Scheme3.

A compound of formula (IIb) in which R₄ represents a halogen atom istreated with triethylamine, and the salt thus obtained is reacted withan acid chloride of formula (IIIa), in which R'₃ is as defined above, toobtain a compound of formula (IVb), from which a compound of formula(VIb) is prepared by the action of phosphorus pentachloride generally ina solvent such as dichloromethane, followed by reaction of the compound(VIb) with a compound of formula (VII) in which R₁ represents a hydrogenatom or a (C₁ -C₄)alkyl group, R₂ represents a straight or branched (C₁-C₄)alkyl group and R₅ represents a hydrogen atom or a straight orbranched (C₁ -C₄)alkyl group, generally in an aprotic solvent such asdichloromethane, then a residue --COR'₃ is removed by treatment in abasic medium such as ammonia in an aprotic solvent, to obtain a compoundof formula (VIII), which is reacted with a compound of formula (IX) inwhich A is as defined above and R is a (C₁ -C₄)alkyl group generally ina solvent such as dimethylformamide in the presence of a ##STR6##catalyst such as tetrakis(triphenylphosphine)palladium (0), to form acompound of formula (X) which is heated to the reflux temperature in anacidic medium, for example in an acetic acid/water mixture, to obtain acompound of formula (Ia), in which R₄ represents a halogen atom. If acompound of formula (Ia) in which R₄ is a hydrogen atom is desired, thecorresponding compound of formula (Ia) in which R₄ is a halogen atom issubjected to a hydrogenolysis.

If a compound of formula (Ia) in which R₂ represents a hydrogen atom isdesired, the corresponding compound of formula (Ia) in which R₂represents a straight or branched (C₁ -C₄)alkyl group is saponifiedunder standard conditions known to those skilled in the art.

For the compounds of formula (I) in which R₃ represents a group--(CH₂)_(n) OCH₃ (where n is 1, 2 or 3) or --CH₂ O(C₂ H₄ O)_(m) CH₃(where m is 1, 2 or 3), it is also possible to prepare a mixed imide,from the compound of formula (IIb), by a method analogous to thatdescribed for the compound of formula (V) in Scheme 1, then the processof Scheme 3 is followed by reacting this mixed imide with the amine offormula (VII).

The compounds of formula (I) or (Ia) obtained in the above processes areoptionally converted into addition salts thereof by known methods.

The present invention also provides an intermediate compound of formula(XI) ##STR7## in which either R₈ represents a hydrogen atom or atrifluoroacetyl group, R₉ represents a group --COR₃ (where R₃ is asdefined above) and R₇ represents a hydroxyl group, or R₈ represents atrifluoroacetyl group, R₉ represents a group --COR₃ and R₇ represents achlorine atom, or R₈ and R₉ each represents a group --COR'₃ (where R'₃is as defined above) and R₇ represents a chlorine atom or a hydroxylgroup, Z represents an iodine atom, a phenyl or heterocyclic groupoptionally substituted with one or more substituents independentlychosen from halogen atoms and straight or branched (C₁ -C₄)alkyl,straight or branched (C₁ -C₄)alkoxy and trifluoromethyl groups, or acyclo(C₅ -C₈)alkyl group, and R₄ is as defined above.

The heterocyclic group is preferably a pyridyl, thienyl or furyl groupoptionally substitued with one or more substituents chosen from halogenatoms and straight or branched (C₁ -C₄)alkyl, straight or branched (C₁-C₄)alkoxy and trifluoromethyl groups.

The starting materials are commercially available or are described inthe literature or may be prepared according to methods which aredescribed therein or which are known to those skilled in the art.

The compounds of formula (II) and their preparation are described inFrench patent application No. FR 94/14129. The compounds of formula(VII) are described in European patent application No. EP 0,643,047.

The examples which follow illustrate the preparation of certaincompounds in accordance with the invention.

The microanalyses and the IR and NMR spectra confirm the structure ofthe compounds obtained.

The compound numbers in the examples refer to those in the table givenlater which illustrates the chemical structures and the physicalproperties of a few compounds according to the invention.

EXAMPLE 1 (COMPOUND NO. 8) ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(1H-imidazol-4-yl)-2- 2- (3-methoxy-1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!-1-oxopentyl!piperidine-2-carboxylatehydrochloride 1.1. N,N-diethylethanamine salt of 2-(3-methoxy-1-oxopropyl)amino! 1,1'-biphenyl!-3-sulphonic acid

To a solution of 1.74 g (7 mmol) of 2-amino 1,1'-biphenyl!-3-sulphonicacid and 1.6 ml (19.5 mmol) of pyridine in 7 ml of dichloromethane isadded dropwise, at 0° C. under a nitrogen atmosphere, a solution of 1.3g (10.5 mmol) of 3-methoxypropionyl chloride in 3 ml of dichloromethane.The reaction medium is left stirring for 2 hours at 0° C., excessmethanol and triethylamine are added and the mixture is thenconcentrated under reduced pressure. The residue is purified bychromatography on a column of silica gel, eluting with amethanol/dichloromethane/triethylamine mixture (2/98/0.001).

2.3 g of product are obtained in the form of a viscous oil which is usedwithout further purification in the following step.

Yield=100%

1.2. N,N-diethylethanamine salt of 2-(3-methoxy-1-oxopropyl)(trifluoroacetyl)amino!1,1'-biphenyl!-3-sulphonic acid

A mixture of 2.3 g (7 mmol) of the N,N-diethylethanamine salt of 2-(3-methoxy-1-oxopropyl)amino! 1,1'-biphenyl!-3-sulphonic acid and 9.8 ml(70 mmol) of trifluoroacetic anhydride is heated for 3 hours at thereflux temperature, and the reaction medium is then concentrated underreduced pressure.

3.8 g of product are obtained in the form of a viscous oil which is usedwithout further purification in the following step.

Yield=100%

1.3. 2- (3-methoxy-1-oxopropyl)(trifluoroacetyl)amino!1,1'-biphenyl!-3-sulphonyl chloride

To a solution of 3.8 g (7 mmol) of the N,N-diethylethanamine salt of 2-(3-methoxy-1-oxopropyl)(trifluoroacetyl)amino!1,1'-biphenyl!-3-sulphonic acid in 14 ml of dichloromethane are added1.75 g (8.4 mmol) of phosphorus pentachloride, the mixture is heated for3 hours at the reflux temperature and is then concentrated under reducedpressure. The residue thus obtained is purified by chromatography on acolumn of silica gel, eluting with dichloromethane.

1.3 g of product are obtained in the form of a viscous oil which is usedwithout further purification in the following step.

Yield=40%

NMR (CDCl₃), 200 Mhz, δ, (ppm): 8.4-8.2 (m, 1H); 7.8-7.6 (m, 2H);7.5-7.3 (m, 3H); 7.3-7.2 (m, 2H); 3.8-3.5 (m, 2H); 3.3 (s, 3H); 3.0-2.7(m, 2H)

1.4. Ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1- 5-(1H-imidazol-4-yl)-2- 2-(3-methoxy-1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulfonyl!amino!-1-oxopentyl!piperidine-2-carboxylatehydrochloride

To a mixture of 1.5 g (2.4 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1--2-amino-1-oxo-5-1-(triphenylmethyl)-1H-imidazol-4-yl!pentyl!-4-ethylpiperidine-2-carboxylatehydrochloride and 0.8 ml (5.8 mmol) of triethylamine in 15 ml ofdichloromethane are added dropwise, at 0° C. under a nitrogenatmosphere, 1.3 g (2.89 mmol) of 2-(3-methoxy-2-propanoyl)(trifluoroacetyl)!amino1,1'-biphenyl!-3-sulphonyl chloride dissolved in 3 ml ofdichloromethane. The reaction medium is left stirring at thistemperature for 6 hours and is then concentrated under reduced pressure.The residue is taken up in 50 ml of ethyl acetate and is then washedsuccessively with 50 ml of aqueous 0.5N hydrochloric acid solution, thenwith 50 ml of 5% sodium hydrogen carbonate solution and then with 50 mlof saturated sodium chloride solution, and is dried over magnesiumsulphate. The residue thus obtained is heated at 90° C. for 2 hours in amixture containing 50 ml of acetic acid and 50 ml of ethanol, and isthen concentrated under reduced pressure. This residue is purified bychromatography on a column of silica gel, eluting with amethanol/dichloromethane mixture (5/95).

1.2 g of product are obtained in base form.

Yield=75%

The hydrochloride is prepared by dissolving 1.2 g (1.8 mmol) of base in36 ml of a solution of isopropanol in 0.1N hydrochloric acid andevaporating under reduced pressure.

Melting point=74° C.

α!_(D) ²⁰ =+60° (c=0.2; methanol)

EXAMPLE 2 (COMPOUND NO. 15) Ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-2- 3'-methyl-2- (1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!-1-oxopentyl!piperidine-2-carboxylatehydrochloride 2.1. N,N-diethylethanamine salt of 2-bis(1-oxopropyl)amino!-3'-methyl 1,1'-biphenyl!-3-sulphonic acid

2.1 g (8 mmol) of 2-amino-3'-methyl 1,1'-biphenyl!-3-sulphonic acid aredissolved in 10 ml of dichloromethane, 1.34 ml (9.6 mmol) oftriethylamine are added and the mixture is evaporated to dryness. Thesalt obtained is then dissolved in 15.5 ml of propionic anhydride, andthe mixture is heated for 8 hours at 100° C. and evaporated to dryness.The residue is purified by chromatography on a column of silica gel,eluting with a dichloromethane/ethanol/triethylamine mixture(98/2/0.001).

3.6 g of product are obtained in the form of a viscous oil which is usedwithout further purification in the following step.

Yield=95%

2.2. 2- bis(1-oxopropyl)amino!-3'methyl 1,1'-biphenyl!-3-sulphonylchloride

To a solution of 3.6 g (7.6 mmol) of the N,N-diethylethanamine salt of2- bis(1-oxopropyl)amino!-3'-methyl 1,1'-biphenyl!-3-sulphonic acid in 8ml of dichloromethane, at 0° C., are added 1.6 g (7.6 mmol) ofphosphorus pentachloride and the mixture is allowed to return to roomtemperature. The mixture is then heated for 4 hours at the refluxtemperature and is then allowed to return to room temperature. Ether isadded, the mixture is filtered, the filtrate is concentrated and theresidue is purified on a column of florisil™, eluting with anether/pentane mixture (1/1). The product is recrystallized from anether/pentane mixture.

1.7 g of product are obtained in the form of whitish crystals.

Yield=58%

Melting point=91° C.

2.3. ethyl 2R- 1(S), 2α, 4β!!-1- 2- 2- bis(1-oxopropyl)amino!-3'methyl1,1'-biphenyl!-3-yl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

787 mg (2 mmol) of 2- bis(1-oxopropyl)amino!-3'methyl1,1'-biphenyl!-3-sulphonyl chloride are dissolved in 8 ml ofdichloromethane and, at 0° C., 1.3 g (2 mmol) of ethyl 2R- 1(S), 2α,4β!!-1- 2-amino-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride and 0.9 ml of triethylamine are added. The reactionmixture is allowed to warm to room temperature, it is evaporated and theresidue is taken up in 100 ml of ethyl acetate. This solution is washedsuccessively with 50 ml of 1N hydrochloric acid solution, 50 ml ofsaturated sodium hydrogen carbonate solution and 50 ml of saturatedsodium chloride solution, dried over magnesium sulphate and thenevaporated to dryness.

1.6 g of product are obtained, which product is used without furtherpurification in the following step.

Yield=84%

2.4. ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-2- 3'-methyl-2- (1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!-1-oxopentyl!piperidine-2-carboxylatehydrochloride

1.6 g (1.7 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2- 2-bis(1-oxopropyl)amino!-3'methyl 1,1'-biphenyl!-3-yl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylateare dissolved in 85 ml of acetic acid and 17 ml of water, and thesolution is heated to the reflux temperature for 6 hours. It isevaporated to dryness and the residue is taken up in 100 ml of ethylacetate and washed successively with 20 ml of saturated sodium hydrogencarbonate solution and 10 ml of saturated sodium chloride solution, andthen evaporated to dryness. The residue is purified by chromatography ona column of silica gel, eluting with a dichloromethane/ethanol mixture(95/5).

1 g of product is obtained in base form.

The hydrochloride is prepared in a solution of isopropanol in 0.1Nhydrochloric acid and is again concentrated under reduced pressure. Thisresidue is purified on an RP18 column, eluting with anacetonitrile/water mixture (1/1).

After freeze-drying, 893 mg of product are obtained.

Yield=67%

Melting point=140° C.

α!_(D) ²⁰ =+115° (c=0.2; methanol)

EXAMPLE 3 (COMPOUND NO. 3) ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-1-oxo-2- 2- (1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!pentyl!piperidine-2-carboxylatehydrochloride

3.1. 2- bis(1-oxopropyl)amino! 1,1'-biphenyl!-3-sulphonyl chloride

The product is prepared according to the method described in Example 2,starting with 2-amino 1,1'-biphenyl!-3-sulphonic acid and propionicanhydride.

Melting point=113.8° C.

3.2. ethyl 2R- 1(S), 2α, 4β!!-1- 2- 2- bis(1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

1.88 g (4.85 mmol) of 2- bis(1-oxopropyl)amino!1,1'-biphenyl!-3-sulphonyl chloride are dissolved in 20 ml ofdichloromethane and the mixture is placed at 0° C. 2.99 g (4.5 mmol) ofethyl 2R- 1(S), 2α, 4β!!-1- 2-amino-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride and, dropwise, 1.6 ml of triethylamine are then added. Themixture is left stirring at this temperature overnight. It isconcentrated under reduced pressure and the residue is taken up in 100ml of ethyl acetate and washed successively with 50 ml of 1Nhydrochloric acid solution, with 50 ml of saturated sodium hydrogencarbonate solution and then with 50 ml of saturated sodium chloridesolution. It is dried over magnesium sulphate and concentrated underreduced pressure. The residue is purified by chromatography on a columnof silica gel, eluting with a dichloromethane/methanol mixture (98/2).

2.9 g of product are obtained.

Yield=62%

3.3. ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-1-oxo-2- 2- (1-oxopropyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!pentyl!piperidine-2-carboxylatehydrochloride

To 2.9 g (3 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2- 2-bis(1-oxopropyl)amino! 1,1'-biphenyl!-3-yl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylateare added 150 ml of acetic acid and 50 ml of water, and the mixture isheated at the reflux temperature for 6.5 hours. It is evaporated todryness and the residue is purified by chromatography on a column ofsilica gel, eluting with a dichloromethane/methanol mixture (95/5).

1.7 g of product are obtained in base form.

The hydrochloride is prepared in 10 ml of a solution of isopropanol in0.1N hydrochloric acid, and the mixture is again concentrated underreduced pressure. This residue is purified on an RP 18 column, elutingwith an acetonitrile/water mixture (1/1).

1.3 g of product are obtained in the form of the hydrochloride.

Yield=63%

Melting point=104°-105° C.

α!_(D) ²⁰ =+105° (c=0.2; methanol)

EXAMPLE 4 (COMPOUND NO. 29) ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-1-oxo-2- 2-(1-oxopropyl)amino!-3-pyrid-2-ylphenyl!sulphonyl!amino!pentyl!piperidine-2-carboxylatehydrochloride 4.1. N,N-diethylethanamine salt of 2-bis(1-oxopropyl)amino!-5-bromo-3-iodobenzenesulphonic acid

A solution of 31.7 g (66 mmol) of the N,N-diethylethanamine salt of2-amino-5-bromo-3-iodobenzenesulphonic acid in 114 ml (1.32 mol) ofpropionyl chloride is heated for 16 hours at the reflux temperature,then the reaction medium is concentrated under reduced pressure and theproduct is crystallized from 100 ml of ethyl acetate.

32.5 g of product are obtained in the form of white crystals.

Yield=84%

Melting point=124°-128° C.

4.2. 2- bis(1-oxopropyl)amino!-5-bromo-3-iodobenzenesulphonyl chloride

To a solution of 32.5 g (55 mmol) of the N,N-diethylethanamine salt of2- bis(1-oxopropyl)amino!-5-bromo-3-iodobenzenesulphonic acid indichloromethane are added portionwise, at 0° C. under nitrogen, 16.8 g(82.4 mmol) of phosphorus pentachloride. The mixture is allowed to warmto room temperature and is heated for 4 hours at the reflux temperature.200 ml of ether are poured in, the mixture is filtered and the filtrateis concentrated. The residue is purified by chromatography on a columnof florisil™ eluting with an ether/hexane mixture (2/8). The product isrecrystallized from an ether/pentane mixture. 12 g of product areobtained in the form of white crystals.

Yield=43%

Melting point=127°-132° C.

4.3. ethyl 2R- 1(S), 2α, 4β!!-1- 2- 5-bromo-3-iodo-2-(1-oxopropyl)amino!phenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

To a solution of 1.28 g (2 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1-2-amino-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride in dichloromethane are successively added, at 0° C. undernitrogen, 1.02 g (2 mmol) of 2-bis(1-oxopropyl)amino!-5-bromo-3-iodobenzenesulphonyl chloride followedby dropwise addition of 0.69 μl (5 mmol) of triethylamine. The reactionmedium is left stirring for 6 hours at 0° C. and is then taken up in 100ml of ethyl acetate. Next, it is washed successively with twice 50 ml of0.5N hydrochloric acid, 50 ml of saturated sodium hydrogen carbonatesolution and 50 ml of saturated sodium chloride solution. Finally, thesolution is dried over magnesium sulphate and concentrated under reducedpressure. 2.1 g of product are obtained in the form of a viscous oil,which is taken up in 100 ml of tetrahydrofuran and treated at 0° C. withammonia gas. The reaction medium is left stirring for 2 hours at thistemperature, and is concentrated under reduced pressure. The residue ispurified by chromatography on a column of silica gel, eluting with adichloromethane/methanol mixture (98/2). 1.4 g of product are obtainedin the form of a viscous oil, which is used without further purificationin the following step.

Yield=70%

4.4. ethyl 2R- 1(S), 2α, 4β!!-1- 2-5-bromo-2-(1-oxopropyl)amino!-3-pyrid-2-ylphenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

A mixture containing 1.2 g (1.2 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2-5-bromo-3-iodo-2- (1-oxopropyl)amino!phenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate,0.53 g (1.44 mmol) of 2-(tributylstannyl)pyridine, 14 mg (0.07 mmol) ofcopper iodide and 83 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium (0) in 2.4 ml of dimethylformamide is heated at 95° C. underargon for 4 hours. The reaction medium is then taken up in 100 ml ofethyl acetate, washed with twice 100 ml of 5% sodium hydrogen carbonatesolution and then with 50 ml of saturated sodium chloride solution,dried over magnesium sulphate and concentrated under reduced pressure.The residue is purified by chromatography on a column of silica gel,eluting with a dichloromethane/methanol mixture (98/2).

0.72 g of product is obtained, which is used without furtherpurification in the following step.

Yield=63%

Melting point=90°-94° C.

4.5. ethyl 2R- 1(S), 2α, 4β!!-1- 2- 5-bromo-2-(1-oxopropyl)amino!-3-pyrid-2-ylphenyl!sulphonyl!amino!-5-5-methyl-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

0.71 g (0.75 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2- 5-bromo-2-(1-oxopropyl)amino!-3-pyrid-2-ylphenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatein a mixture containing 35 ml of acetic acid and 10 ml of water isheated at 100° C. for 1 hour. The reaction medium is concentrated underreduced pressure and the residue is purified by chromatography on acolumn of silica gel, eluting with a methanol/dichloromethane mixture(5/95).

0.452 g of product is isolated in the form of a viscous oil, which isused without further purification in the following step.

Yield=83%

4.6. Ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-1-oxo-2- 2-1-oxopropyl)amino!-3-pyrid-2-ylphenyl!sulphonyl!amino!pentyl!piperidine-2-carboxylatehydrochloride

A mixture of 0.45 g (0.61 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2-5-bromo-2- (1-oxopropyl)amino!-3-pyrid-2-ylphenyl!sulphonyl!amino!-5-5-methyl-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate,0.39 g (6 mmol) of ammonium formate and 50 mg of 10% palladium oncharcoal in 8 ml of methanol and 0.2 ml of acetic acid is heated for 4hours at the reflux temperature. The reaction medium is thenconcentrated under reduced pressure and the residue is purified bychromatography on a column of silica gel, eluting with adichloromethane/methanol mixture (95/5).

0.36 g of product is obtained in the form of a viscous oil.

Yield=81%

The hydrochloride is prepared according to the method described inExample 3.

Melting point=78°-84° C.

α!_(D) ²⁰ =+91° (c=0.2; methanol)

EXAMPLE 5 (COMPOUND NO. 25) Ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-2- 3',5'-dimethyl-2-(1-oxobutyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!-1-oxopentyl!piperidine-2-carboxylatehydrochloride 5.1. N,N-diethylethanamine salt of 2-(3',5'-dimethyl)-2-(1-oxobutyl)amino! 1,1'-biphenyl!-3-sulphonic acid

2 g (7.2 mmol) of 2-amino-3',5'-dimethyl 1,1'-biphenyl!-3-sulphonic acidin 8.3 ml (50 mmol) of butyric anhydride are heated for 2 hours at 80°C. The medium is allowed to warm to room temperature and is concentratedunder reduced pressure. The residue is purified by chromatography on anRP 18 column, eluting with an acetonitrile/water mixture (2/8).

1.5 g of product are obtained in the form of a white solid. Thetriethylamine salt is prepared according to the method described inExample 2, and is used without further purification in the followingstep.

Yield=60%

5.2. N,N-diethylethanamine salt of 2- (3',5'-dimethyl)-2-(1-oxobutyl)(trifluoroacetyl)amino! 1,1'-biphenyl!-3-sulphonic acid

A mixture of 1.48 g (3.3 mmol) of the N,N-diethylethanamine salt of 2-(3',5'-dimethyl)-2-(1-oxobutyl)amino! 1,1'-biphenyl!-3-sulphonic acidand 4.7 ml (33 mmol) of trifluoroacetic anhydride is heated at thereflux temperature for 1 hour, and the reaction medium is thenconcentrated under reduced pressure.

1.8 g of product are obtained in the form of a viscous oil, whichproduct is used without further purification in the following step.

Yield=100%

5.3. 2- (3',5'-dimethyl)-2- (1-oxobutyl)(trifluoroacetyl)amino!1,1'-biphenyl!-3-sulphonyl chloride

To a solution of 1.8 g (3.3 mmol) of the N,N-diethylethanamine salt of2- (3',5'-dimethyl)-2- (1-oxobutyl)(trifluoroacetyl)amino!1,1-biphenyl!-3-sulphonic acid in 10 ml of dichloromethane are added, atroom temperature under nitrogen, 1.37 g (6.6 mmol) of phosphoruspentachloride, the mixture is heated at the reflux temperature for 4hours and the reaction medium is then allowed to cool to roomtemperature, 100 ml of ether are poured in and the mixture is filteredthen concentrated under reduced pressure. The residue thus obtained ispurified by chromatography on a florisil™ column, eluting withdichloromethane.

0.78 g of product is obtained in the form of a viscous oil, which isused without further purification in the following step.

Yield=51%

NMR (CDCl₃), 200 Mhz, δ, (ppm): 8.3 (dd, 1H, J=6.5 Hz, J=0.7 Hz);7.85-7.7 (m, 2H); 7.15-7.00 (m, 1H), 6.8 (s, 2H); 2.5-2.3 (m, 7H);1.75-1.5 (m, 3H); 0.9 (t, 3H, 6Hz)

5.4. ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-2- 3',5'-dimethyl-2-(1-oxobutyl)amino!1,1'-biphenyl!-3-yl!sulphonyl!amino!-1-oxopentyl!piperidine-2-carboxylatehydrochloride

To a solution of 0.554 g (1.2 mmol) of 2- (3',5'-dimethyl)-2-(1-oxobutyl)(trifluoroacetyl)amino! 1,1'-biphenyl!-3-sulphonyl chloridein 5 ml of dichloromethane is added, at 0° C. under nitrogen, 0.815 g(1.2 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2-amino-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride followed by dropwise addition of 0.56 ml (4 mmol) oftriethylamine. The reaction medium is left stirring at this temperaturefor 6 hours and is then concentrated under reduced pressure. The residueis taken up in 100 ml of ethyl acetate and is then washed successivelywith 50 ml of aqueous 0.5N hydrochloric acid solution, then with 50 mlof aqueous 5% sodium hydrogen carbonate solution and then with 50 ml ofsaturated sodium chloride solution, and dried over magnesium sulphate.The organic phase is concentrated under reduced pressure.

1 g of product is obtained, which is used without further purificationin the following step.

The residue is heated for 2 hours at the reflux temperature in a mixturecontaining 12 ml of acetic acid, 6 ml of tetrahydrofuran and 6 ml ofwater, and the reaction medium is then concentrated under reducedpressure. The residue is purified on a column of silica, eluting with amethanol/water mixture (5/95).

0.475 g of product is obtained in base form in the form of a viscousoil.

Yield=56%

The hydrochloride is prepared by dissolving 0.475 g of base in 14 ml ofa solution of isopropanol in 0.1N hydrochloric acid.

Melting point=135° C.

α!_(D) ²⁰ =+118° (c=0.2; methanol)

EXAMPLE 6 (COMPOUND NO. 34) ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-1-oxo-2- 2-(1-oxopropyl)amino!-3-thien-2-ylphenyl!sulphonyl!amino!pentyl!piperidine-2-carboxylatehydrochloride 6.1. N,N-diethylethanamine salt of 2-bis(1-oxopropyl)amino!-3-thien-2-ylbenzenesulphonic acid

1.9 g (7.8 mmol) of 2-amino-3-thien-2-ylbenzenesulphonic acid aredissolved in 10 ml of dichloromethane, 1.3 ml (9.4 mmol) oftriethylamine are added and the mixture is evaporated to dryness. Thesalt obtained is then dissolved in 15 ml of propionic anhydride, and themixture is heated for 8 hours at 150° C. and evaporated to dryness. Theresidue is purified by chromatography on a column of silica gel, elutingwith a dichloromethane/ethanol/triethylamine mixture (98/2/0.001).

2.76 g of product are obtained after recrystallization from ethylacetate.

Yield=79%

6.2. 2- bis(1-oxopropyl)amino!-3-thien-2-ylbenzenesulphonyl chloride

To a solution of 2.8 g (6.1 mmol) of the N,N-diethylethanamine salt of2- bis(1-oxopropyl)amino!-3-thien-2-ylbenzenesulphonic acid in 6 ml ofdichloromethane are added, at 0° C., 1.3 g (6.1 mmol) of phosphoruspentachloride and the reaction mixture is allowed to warm to roomtemperature. The mixture is then heated for 5 hours at the refluxtemperature and then allowed to cool to room temperature. Ether isadded, the mixture is filtered and the residue is precipitated from anether/pentane mixture (1/1). The mixture is filtered and the filtrate isconcentrated under reduced pressure and purified by chromatography on acolumn of florisil™. 2.2 g of product are obtained, which product iscrystallized from an ether/pentane mixture.

1.5 g of product are obtained in the form of white crystals.

Yield=55%

Melting point=113.6° C.

6.3. ethyl 2R- 1(S), 2α, 4β!!-1-2- 2-bis(1-oxopropyl)amino!-3-thien-2-ylphenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

0.9 g (2 mmol) of 2- bis(1-oxopropyl)amino!-3-thien-2-ylbenzenesulphonylchloride is dissolved in 8 ml of dichloromethane and the mixture isplaced at 0° C. 1.3 g (2 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2-amino-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride are then added, followed by dropwise addition of 0.9 ml oftriethylamine. The mixture is left stirring at this temperatureovernight. It is concentrated under reduced pressure and the residue istaken up in 100 ml of ethyl acetate and washed successively with 50 mlof 1N hydrochloric acid solution, with 50 ml of saturated sodiumhydrogen carbonate solution and then with 50 ml of saturated sodiumchloride solution. The solution is dried over magnesium sulphate andconcentrated under reduced pressure. The residue is purified bychromatography on a column of silica gel, eluting with adichloromethane/methanol mixture (98/2).

2 g of product are obtained, which product is used without furtherpurification in the following step.

6.4. ethyl 2R- 1(S), 2α, 4β!!-4-ethyl-1-5-(5-methyl-1H-imidazol-4-yl)-1-oxo-2- 2-(1-oxopropyl)amino!-3-thien-2-ylphenyl!sulphonyl!amoino!pentyl!piperidine-2-carboxylatehydrochloride

To 1.9 g (2 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1- 2- 2-bis(1-oxopropyl)amino!-3-thien-2-ylphenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylateare added 100 ml of acetic acid and 20 ml of water, and the mixture isheated at the reflux temperature for 6 hours. It is evaporated todryness and the residue is taken up in 100 ml of ethyl acetate andwashed with 10 ml of saturated sodium hydrogen carbonate solution andthen with 10 ml of saturated sodium chloride solution, dried overmagnesium sulphate and evaporated to dryness. The residue is purified bychromatography on a column of silica gel, eluting with adichloromethane/methanol gradient.

1.1 g of product are obtained in base form.

The hydrochloride is prepared in 10 ml of a solution of isopropanol in0.1N hydrochloric acid, and is again concentrated under reducedpressure. This residue is purified on an RP 18 column, eluting with anacetonitrile/water mixture (1/1).

After freeze-drying, 0.939 g of product is obtained in the form of thehydrochloride.

Yield=67%

Melting point=151° C.

α!_(D) ²⁰ =+107° (c=0.2; methanol)

EXAMPLE 7 (COMPOUND NO. 42) ethyl 2R- 1(S), 2α, 4β!!-1- 2-2-(acetylamino)-3-cyclopentylphenyl!sulphonyl!amino!-5-(5-methyl-1H-imidazol-4-yl)-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride 7.1. N,N-diethylethanamine salt of2-(diacetylamino)-3-cyclopentylbenzenesulphonic acid

3.42 g (10 mmol) of the N,N-diethylethanamine salt of2-amino-3-cyclopentylbenzenesulphonic acid dissolved in 100 ml of acetylchloride are heated at the reflux temperature for 48 hours, and thereaction medium is then concentrated under reduced pressure.

4.3 g of product are obtained in the form of an oil, which product isused without further purification in the following step.

Yield=100%

7.2. 2-(diacetylamino)-3-cyclopentylbenzenesulphonyl chloride

A solution of 1.55 g (3.6 mmol) of2-(diacetylamino)-3-cyclopentylbenzenesulphonic acid and 1.12 g (5.4mmol) of phosphorus pentachloride in 10 ml of dichloromethane is heatedat the reflux temperature for 2.5 hours, and the reaction medium is thenconcentrated under reduced pressure. The residue thus obtained ispurified by chromatography on a column of florisil™, eluting withdichloromethane.

0.62 g of product is obtained in the form of a viscous oil, which isused without further purification in the following step.

Yield=50%

7.3. ethyl 2R- 1(S), 2α, 4β!!-1- 2-2-(diacetylamino)-3-cyclopentylphenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylate

To a mixture of 0.77 g (1.2 mmol) of ethyl 2R- 1(S), 2α, 4β!!-1-2-amino-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride and 0.37 ml (2.64 mmol) of triethylamine in 5 ml ofdichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere,0.35 g (1 mmol) of 2-(diacetylamino)-3-cyclopentylbenzenesulphonylchloride dissolved in 1 ml of dichloromethane. The reaction medium isleft stirring at this temperature for 6 hours and is then concentratedunder reduced pressure. The residue is taken up in 50 ml of ethylacetate and is then washed successively with 50 ml of aqueous 0.5Nhydrochloric acid solution, with 50 ml of saturated sodium hydrogencarbonate solution and then with 50 ml of saturated sodium chloridesolution, and dried over magnesium sulphate. The organic phase isconcentrated under reduced pressure.

The residue is used without further purification in the following step.

7.4. ethyl 2R- 1(S), 2α, 4β!!-1- 2-2-(acetylamino)-3-cyclopentylphenyl!sulphonyl!amino!-5-(5-methyl-1H-imidazol-4-yl)-1-oxopentyl!-4-ethylpiperidine-2-carboxylatehydrochloride

ethyl 2R- 1(S), 2α, 4β!!-1- 2-2-(diacetylamino)-3-cyclopentylphenyl!sulphonyl!amino!-5-5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl!-1-oxopentyl!-4-ethylpiperidine-2-carboxylateis heated for 48 hours at the reflux temperature, in a mixturecontaining 8 ml of acetic acid, 4 ml of tetrahydrofuran and 4 ml ofwater, and the reaction medium is then concentrated under reducedpressure. The residue is taken up in 18 ml of a solution of isopropanolin 0.1N hydrochloric acid and is again concentrated under reducedpressure. This residue is purified on an RP 18 column, eluting with anacetonitrile/water mixture (6/4).

0.31 g of product is obtained in the form of the hydrochloride.

Yield=50%

Melting point=140° C.

α!_(D) ²⁰ =+74.5° (c=0.25; methanol)

Key to the table: in the "salt" column: "chlor." represents ahydrochloride. The absence of an entry corresponds to the product inbase form. In the " α!_(D) ²⁰ " column: c=0.2 except where otherwisementioned; solvent=methanol.

                                      TABLE                                       __________________________________________________________________________     ##STR8##                                                                     No.                                                                              R.sub.1                                                                            R.sub.2                                                                            R.sub.3    R.sub.4                                                                          R.sub.5                                                                            A         Salt m.p. (°C.)                                                                   α!.sub.D.sup.20                                                         (°)               __________________________________________________________________________    1  CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR9## chlor.                                                                             136-141                                                                            +128.8 (c = 0.25)         2  CH.sub.3                                                                           H    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR10##                                                                              chlor.                                                                             165-170                                                                            +92.4 (c = 0.25)          3  CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR11##                                                                              chlor.                                                                             104-105                                                                            +105                      4  CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR12##                                                                              chlor.                                                                             95   +109.5                    5  H    C.sub.2 H.sub.5                                                                    CH.sub.3   H  CH.sub.3                                                                            ##STR13##                                                                              chlor.                                                                             125  +103                      6  H    H    CH.sub.3   H  CH.sub.3                                                                            ##STR14##                                                                              chlor.                                                                             168-175                                                                            +68.4 (c = 0.25)          7  H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.4 OCH.sub.3                                                                Br C.sub.2 H.sub.5                                                                     ##STR15##                                                                              chlor.                                                                             120  +52.5                     8  H    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.4 OCH.sub.3                                                                H  C.sub.2 H.sub.5                                                                     ##STR16##                                                                              chlor.                                                                             74   +60                       9  H    H    C.sub.2 H.sub.4 OCH.sub.3                                                                H  C.sub.2 H.sub.5                                                                     ##STR17##                                                                              chlor.                                                                             132  +59                       10 H    C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          Br C.sub.2 H.sub.5                                                                     ##STR18##                                                                              chlor.                                                                             121  +83                       11 H    C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR19##                                                                              chlor.                                                                             125-127                                                                            +124                      12 H    H    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR20##                                                                              chlor.                                                                             141  +116                      13 H    C.sub.2 H.sub.5                                                                    CH.sub.2 O(C.sub.2 H.sub.4 O).sub.2 CH.sub.3                                             H  C.sub.2 H.sub.5                                                                     ##STR21##                                                                              chlor.                                                                             74   +77                       14 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR22##                                                                              chlor.                                                                             134  +113                      15 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR23##                                                                              chlor.                                                                             140  +115                      16 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR24##                                                                              chlor.                                                                             120  +112.5                    17 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR25##                                                                              chlor.                                                                             128  +94                       18 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR26##                                                                              chlor.                                                                             130  +110                      19 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR27##                                                                              chlor.                                                                             136  +110                      20 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR28##                                                                              chlor.                                                                             108  +103                      21 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR29##                                                                              chlor.                                                                             154  +103                      22 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR30##                                                                              chlor.                                                                             126  +54                       23 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR31##                                                                              chlor.                                                                             65   +104.5                    24 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR32##                                                                              chlor.                                                                             128  +54                       25 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR33##                                                                              chlor.                                                                             135  +118                      26 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR34##                                                                              chlor.                                                                             130  +125                      27 H    C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR35##                                                                              chlor.                                                                             131  +42.5                     28 H    H    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR36##                                                                              chlor.                                                                             172  +57                       29 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR37##                                                                              chlor.                                                                             78-84                                                                              91                        30 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR38##                                                                              chlor.                                                                             178.2                                                                              +97.6 (c = 0.25)          31 CH.sub.3                                                                           H    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR39##                                                                              chlor.                                                                             150-155                                                                            +111 (c = 0.55)           32 H    C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR40##                                                                              chlor.                                                                             90   +73                       33 H    H    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR41##                                                                              chlor.                                                                             150  +82.5                     34 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR42##                                                                              chlor.                                                                             151  +107                      35 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR43##                                                                              chlor.                                                                             124  +101                      36 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR44##                                                                              chlor.                                                                             110  +52.6                     37 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR45##                                                                              chlor.                                                                             132  +63                       38 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  CH.sub.3                                                                            ##STR46##                                                                              chlor.                                                                             130-132                                                                            +132                      39 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR47##                                                                              chlor.                                                                             128-134                                                                            +57                       40 H    C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR48##                                                                              chlor.                                                                             124  +78                       41 H    H    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR49##                                                                              chlor.                                                                             149  +102                      42 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR50##                                                                              chlor.                                                                             140  +74.5                     43 CH.sub.3                                                                           H    CH.sub.3   H  C.sub.2 H.sub.5                                                                     ##STR51##                                                                              chlor.                                                                             160  +81.5                     44 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          H  C.sub.2 H.sub.5                                                                     ##STR52##                                                                              chlor.                                                                             118  +93                       45 H    C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR53##                                                                              chlor.                                                                             125  +73.5                     46 CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  CH.sub.3                                                                            ##STR54##                                                                              chlor.                                                                             132  +104                      47 H    C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                          H  C.sub.2 H.sub.5                                                                     ##STR55##                                                                              chlor.                                                                             120  +77                       __________________________________________________________________________

The compounds of the invention formed the subject of pharmacologicalstudies which demonstrated their antithrombotic properties and theiradvantage as substances having therapeutic activity.

1. Determination of the Inhibition Constants (Ki) With Respect toThrombin

25 μl of a solution of test compound (7 concentrations are studied), 50μl of a solution of chromogenic substrate (2 concentrations are studied;S2238 Chromogenix™) dissolved in Tris buffer at pH 7.5 (50 mM Tris, 100mM NaCl and 0.1% BSA) and finally 25 μl of a 300 U/ml thrombin solutionare placed in each well of a 96-well microplate. The release of4-nitroaniline is monitored at 405 nm using a plate reader.

The K_(i) is determined according to the Dixon method.

The compounds of the invention are thrombin inhibitors and their K_(i)is between 0.001 and 100 μM.

2. Ex Vivo Coagulation of Rat Plasma by Human Thrombin

Male CD rats weighing 150 to 200 g are treated with the test compound orwith the vehicle, via the i.v., oral or subcutaneous route. The animalsare then anaesthetized with Nembutal™ (60 mg/kg; 0.1 ml/kg), the bloodis withdrawn over 3.8% trisodium citrate (1 vol/9 vol of blood) from theretroorbital sinus and the plasma is prepared by centrifugation at 3600g for 15 minutes at room temperature. 200 μl of plasma are thenincubated at 37° C. with 200 βl of a solution of human thrombin, thefinal human thrombin concentration being 0.75 NIH units/ml, and thecoagulation time is noted. The anticoagulant effect is expressed as thedose which increases the coagulation time by 100%. The compounds of theinvention inhibit the coagulation of rat plasma at doses of from 0.01 to5 mg/kg i.v. They are also active via the oral and subcutaneous routes.

3. Aggregation of Rabbit Platelets Induced by Human Thrombin

The blood is withdrawn by cardiac puncture onto 3.8% trisodium citrate(1 vol/9 vol of blood). It is centrifuged at 250 g for 10 minutes. Theplatelet-rich plasma (P₃ P) thus obtained is withdrawn and the plateletsare counted.

2 ng/ml of prostacyclin dissolved in ice-cold Tris buffer at pH 9.0 areadded to the P₃ P. The mixture is centrifuged at 110 g for 10 minutesand is decanted. Further prostacyclin, dissolved in 50 mM sodiumhydroxide at pH 12, is added, so as to have a final concentration of 200ng/ml. The P₃ P is again centrifuged, at 800 g for 10 minutes. Theplatelet-poor plasma is removed and the pellet is suspended in a volumeof tyrode containing 200 ng/ml of prostacyclin, this volume being equalto the initial volume of P₃ P. This suspension is centrifuged at 800 gfor 10 minutes. Suspension of the pellet and centrifugation are repeatedunder the same conditions. The final pellet is suspended in aprostacyclin-free tyrode solution and is left to stand for 2 hours inorder to allow complete removal of the prostacyclin. The aggregation ofthese platelets is induced with human thrombin to the finalconcentration of 0.3 NIH units/ml. The variations in optical density arerecorded using a 4-channel aggregometer. The test compound or itsvehicle is added to the platelet suspension (maximum volume of 3 μladded), 2 minutes before the addition of thrombin. The concentrationwhich inhibits the aggregation by 50% (IC₅₀) is determined.

The compounds of the invention may be useful in all the clinicalindications associated with thrombosis or in those in which thromboticcomplications may be involved.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) and a pharmaceutically acceptableexcipient. This composition may be provided in all forms suitable fororal, parenteral or intravenous administration, such as a tablet,dragee, gelatin capsule, wafer capsule, injectable or drinkable solutionor suspension. All of these forms are dosed to allow an administrationof 1 to 1000 mg per day and per patient, in one or more doses.

The present invention also provides a compound of formula (I) for use ina method of treatment of the human or animal body.

The present invention further provides the use of a compound of formula(I) in the manufacture of a medicament for the treatment of thrombosisor thrombotic complications.

There is also disclosed a method of treating or preventing thrombosis orthrombotic complications in a subject which comprises administering tothat subject an effective amount of a compound of formula (I).

We claim:
 1. A compound of formula (XI) ##STR56## in which (1) R₈represents a hydrogen atom or a trifluoroacetyl group, R₉ represents agroup --COR₃ where R₃ is a straight or branched (C₁ -C₇)alkyl group, agroup --(CH₂)_(n) OCH₃ (where n is 1, 2 or 3) or a group --CH₂ O(C₂ H₄O)_(m) CH₃ (where m is 1, 2 or 3) and R₇ represents a hydroxyl group,or(2) R₈ represents a trifluoroacetyl group, R₉ represents a group--COR₃ and R₇ represents a chlorine atom, or (3) R₈ and R₉ eachrepresents a group --COR'₃ where R'₃ is a straight or branched (C₁-C₇)alkyl group and R₇ represents a chlorine atom or a hydroxyl group,Zrepresents an iodine atom, a phenyl or 5- to 6-membered heterocyclicring having one or more heteroatoms which may be the same or differentselected from the group consisting of nitrogen, oxygen and sulfur, thephenyl or the heterocyclic ring being optionally substituted with one ormore substituents independently chosen from halogen atoms and straightor branched (C₁ -C₄)alkyl, straight or branched (C₁ -C₄)alkoxy andtrifluoromethyl groups, or a cyclo(C₅ -C₈)alkyl group, and R₄ is ahydrogen atom or a halogen atom.